Efficacy of generic sofosbuvir with daclatasvir compared to sofosbuvir/ledipasvir in genotype 4 hepatitis C virus: A prospective comparison with historical control.

Background and Aim: Management of genotype 4 hepatitis C virus (HCV) has shifted to interferon-free regimens with a high sustained virological response (SVR-12), especially with NS5B/NS5A inhibitor combinations such as sofosbuvir and ledipasvir (Sof-Led). The guidelines have recommended the combination of sofosbuvir and another NS5A inhibitor, daclatasvir, to manage HCV genotypes 1-3. However, its use was extended to genotype 4 HCV based on extrapolating evidence. Our aim is to assess the efficacy of generic sofosbuvir + branded daclatasvir (Sof-Dac) compared to the Sof-Led combination in treating genotype 4 HCV. Methods: This study is an open-label, 2-period, noninferiority study that compared patients receiving a combination of generic sofosbuvir 400 mg and daclatasvir 60 mg orally daily (Group 2) prospectively to a historical control (Group 1) that included patients who received a combination of sofosbuvir/ledipasvir 400/90 mg orally daily. The primary endpoint is the proportion of patients who achieved SVR-12. Results: The study included 111 patients in the (Sof-Led) Group 1 and 109 patients (Sof-Dac) Group 2. For the primary outcome, SVR-12 was achieved in 106 (95.5%) of the patients in Group 1 versus 108 (99.1%) in Group 2 (p = 0.2). In addition, all patients who achieved SVR-12 also achieved SVR-24. Conclusion: Generic sofosbuvir combined with branded daclatasvir was safe and effective for treating genotype 4 HCV compared to Sof-Led. This combination may significantly reduce the cost burden, enabling a larger pool of treated patients. Office of research affairs at KFSHRC RAC# 2171 036.

Predictors of sustained virological response to a 48-week course of pegylated interferon alfa-2a and ribavirin in patients infected with hepatitis C virus genotype 4.

BACKGROUND AND OBJECTIVES: Knowledge of the predictors of sustained viral response (SVR) to pegylated interferon (PEG-INF) alfa-2a and ribavirin (RBV) therapy in patients with hepatitis C genotype-4 (HCV-4) is crucial for selecting patients who would benefit most from therapy. We assessed the predictors of SVR to this combination therapy in Saudi patients with chronic HCV-4 infection. PATIENTS AND METHODS: This retrospective study included 148 patients with HCV-4 infection who underwent clinical, biochemical and virological assessments before treatment and at 12, 24, 48 and 72 weeks post-treatment. RESULTS: Of the 148 patients, 90 (60.8%) were males. Mean (SD) for age was 48.5 (12.7) years and BMI was 27.9 (7.5) kg/m(2). Seventy-nine of 148 (60.1%) patients were treatment naïve and 110 (74.3%) underwent pre-treatment liver biopsy. Eighteen (12.2%) patients did not complete therapy because of side effects or they were lost to follow up. Early virological response was achieved in 84 of 91 (92.3%) patients. In the 130 (87.8%) patients who completed therapy, 34 (26.2%) were non-responders and 96 (63.8%) achieved end-of-treatment virological response (ETVR). SVR and virological relapse (24 weeks after ETVR) occurred in 66/130 (50.7%) and 30/130 (31.2%) patients, respectively. Compared to relapsers, sustained responders were significantly younger (P=.005), non-diabetic (P=.005), had higher serum albumin (P=.028), lower alpha-fetoprotein level (P=.026), lower aspartate aminotransferase (AST) (P=.04) levels, and were treatment-naïve (P=.008). In a multivariate regression analysis, the independent predictors of SVR were younger age (P=.016), lower serum AST (P=.012), and being treatment naïve (P=.021). CONCLUSION: Approximately half of HCV-4 patients who complete the course of combination therapy achieve an SVR, especially if they are young, treatment naA ve and have lower AST levels.

HBsAg clearance in chronic hepatitis B patients with add-on pegylated interferon alfa-2a to ongoing tenofovir treatment: A randomized controlled study.

BACKGROUND/AIMS: The ideal end point of treatment for chronic hepatitis B virus (HBV) infection is sustained off-therapy hepatitis B surface antigen (HBsAg) loss with or even without seroconversion to anti-HBs. We investigated the role of adding PEGylated interferon (PEG IFN) to ongoing tenofovir treatment in chronic HBV patients for achieving HBsAg clearance. PATIENTS AND METHODS: In this randomized controlled trial, chronic HBV patients who have been receiving tenofovir for >6 months with HBV viral load <2000 IU/ml were randomized into two groups. One group (add-on therapy) was given subcutaneous PEG IFN 180 mcg weekly for 12 months in addition to tenofovir. Patients in the other group received only tenofovir 300 mg orally on a daily basis. Patients in both groups were followed up for a total of two years, and patients in both groups were given tenofovir 300 mg daily indefinitely until they developed HBsAg clearance. RESULTS: Twenty-three patients were allocated to the PEG IFN and tenofovir (add-on therapy) group, and another 25 patients were recruited to the tenofovir monotherapy group. Before randomization, patients had received tenofovir for 1135 mean days (range203 to 1542 days). One patient (4.3%) in add-on therapy lost HBsAg and seroconverted. Within two years, mean HBsAg decreased significantly with add-on therapy (from 4753 IU/ml to 2402; P= 0.03); and it decreased from 5957 IU/ml to 4198; P= 0.09 in tenofovir monotherapy group. More patients in the add-on group developed serious side effects, with treatment discontinuation, and dose reductions (P = 0.3). CONCLUSION: PEG IFN and tenofovir add-on therapy was successful in achieving HBsAg clearance and seroconversion in 4.3% of the patients. Add-on therapy patients had a significant decrease in HBsAg levels in two years; and no significant decrease in HBsAg levels with the tenofovir monotherapy. With no significant HBsAg clearance, the utility of this combination regimen is questionable.

The natural history of hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is a major health problem worldwide. The natural history of HCV infection is not fully understood. For years, there has been an overestimation of the rate of chronicity in acute HCV. Similar high rates of progression to cirrhosis in chronic HCV were reported. The source of confusion stems from the fact that most acute HCV infections are asymptomatic and never come to medical attention. The consequence of this is that most early studies of natural history reflect the more severe end of the spectrum of the disease. Recent studies reported 43-45% rate of chronicity as opposed to the old rates of 77-85%. Also, the rate of progression to cirrhosis and hepatocellular carcinoma was found to be much lower than previously reported. Multiple factors contribute to the chronicity and progression to cirrhosis, the most important being male gender, age, alcohol intake, and the degree of liver fibrosis on initial biopsy. At least 38% of patients with HCV will manifest symptoms of at least one extrahepatic complication. The most important extrahepatic manifestation is mixed cryoglobulinemia. Other extrahepatic manifestations and their response to antiviral therapy are discussed.

Entecavir for the treatment of real-life chronic hepatitis B patients: a study from Saudi Arabia.

BACKGROUND AND OBJECTIVES: Entecavir is a nucleoside analog used in the treatment of chronic hepatitis B. The efficacy of ETV has not been studied in the Saudi population. The objective of the study was to find undetectable HBV DNA after 48 weeks completion of ETV treatment in real-life versus clinical trial patients. DESIGN AND SETTING: A retrospective study in a tertiary care center in Saudi Arabia of patients treated from 2006 January to 2010 June. PATIENTS AND METHODS: Of 43 eligible patients, 24 patients were treatment-naïve and 19 were treatment refractory. RESULTS: Mean HBV DNA viral load was 51 million IU/mL prior to treatment and decreased to 0.16 million IU/mL at 48 weeks. Mean HBV DNA log10 IU/mL was 6.3 before treatment and decreased to 2.3 log10 IU/mL(P=.001) at 48 weeks. After 48 weeks treatment, ALT significantly decreased from a mean ALT of 88.7 U/L before treatment to 37.5U/L (P=.04). After 48 weeks, the HBV DNA was undetectable in 14 (58.4%) in treatment-naïve patients and in 6 (31.6%) treatment-refractory patients. At 48 weeks 17 (60.7%) of HBeAg-negative patients and 3 (20%) HBeAg-positive patients achieved undetectable HBV DNA (P=.003). When the treatment was extended for a median of 24 months (range 12 months to 60 months), 29 (67.4%) achieved undetectable HBV DNA. Among 29 patients who achieved undetectable HBV DNA, the treatment refractory patients reached undetectability within a mean of 32.4 (18.6) months and treatment-naïve patients in a mean of 18.8 (10.5) months(P=.01). Two (13.3%) of HBeAg-reactive patients converted to HBeAg-negative status and one patient (2.3%)lost HBsAg. CONCLUSION: After treatment with entecavir, HBV DNA undetectable at 48 weeks in 58.4% of naïve patients.The response rate was better in HBeAg-negative and treatment-naïve patients compared to HBeAg-positive and treatment-refractory patients.

HCV genotypes among 1013 Saudi nationals: a multicenter study.

BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) genotype (G) knowledge is essential for determining type, duration and rate of response to antiviral therapy, possible route of HCV transmission, and future vaccine development. Our aim was to study HCV genotypes and to provide precise data on genotype distribution in both genders and different age groups amongst Saudi patients. DESIGN AND SETTING: Genotype data from molecular laboratories at four different tertiary care hospitals in Riyadh from January 2006 until December 2010 were collected and analyzed. PATIENTS AND METHODS: Consecutive data on genotype, sex and age was collected from 1013 Saudi patients. Genotyping was done by selective hybridization of amplicons to HCV genotype-specific oligonucleotides. RESULTS: We found G1 in 262 patients (25.9%), G2 in 44 (4.4 %), G3 in 29 (2.9 %), G4 in 608 (60%), and 3 patients (0.3%) each of G5 and G6. In addition, 64 (6.3%) patients had mixed genotypes, mostly G4 and G1. On subtyping in 191 G1 patients, 67 (35.1%) were G1a, and 124 (64.9 %) G1b. Age distribution showed that 18 (1.7%) were 0-20 years, 173 (17.1 %) 21-40 years, 521 (51.4%) 41-60 years and 301(29.7%) > 60 years. There was no significant difference in frequency of G1, G3 and G4 among the two genders. CONCLUSION: G1 and G4 are the predominant genotypes in Saudi patients infected with HCV (85.9%), with a similar distribution among the two sexes and no significant changes in genotype distribution over the past decade.

Wilson disease in 71 patients followed for over two decades in a tertiary center in Saudi Arabia: a retrospective review.

BACKGROUND AND OBJECTIVES: Wilson disease (WD) is a rare autosomal recessive disease. Our objective was to describe the diverse patterns, therapies, and outcomes of this disease. DESIGN AND SETTING: A retrospective study over two decades on WD patients in a tertiary care center in Saudi Arabia. PATIENTS AND METHODS: Clinical and laboratory findings of 71 patients with WD were retrieved from their charts, referral notes and our hospital electronic records and were analyzed. RESULTS: The mean age and standard deviation was 16.8 (10.7) years and 56.5% were males. The main manifestations of WD were hepatic, neurological, and mixed in 39 (54.9%), 12 (16.9%), and 20 (28.2%) patients, respectively, and 11 (15.5%) were asymptomatic cases detected by family screening. A family history of WD was positive in 41 (57.7%) patients, and consanguinity of parents was found in 26 (36.6%) patients. The mean (SD) follow-up period was 92.2 (72.9) (range, 1-320) months. Ten (14.1%) patients died during follow up, while 45 (63.4%) and 16 (22.5%) were still on or lost from follow-up, respectively. The mean (SD) age at the end of follow-up was 25.3 (12) (range, 4-62) years. Hepatoma was discovered in 5 (7.0%) patients. Penicillamine therapy was used by 58 (81.7%) patients, while zinc and trientine were given to 32 (45.1%) and 11 (15.5%) patients, respectively. Sixteen (22.5%) patients underwent liver transplantation and one died (1.4%) on the waiting list. The liver condition remained stable or improved in 35 (49.3%), and the neurological status showed improvement in 11 (34.4%) of the 32 patients who had neurological involvement. CONCLUSIONS: This is the biggest cohort to be reported from the Middle East. WD presentation and outcome of WD are very diverse, and its diagnosis still depends on clinical, laboratory, and radiological evidence of abnormal copper metabolism. WD should be considered in patients of any age with obscure hepatic and/or neurological abnormalities.

Bio-enteric intragastric balloon in obese patients: a retrospective analysis of King Faisal Specialist Hospital experience.

BACKGROUND: Bio-enteric intragastric balloon (BIB) insertion is gaining popularity for weight reduction in obese patients. We evaluated the efficacy, tolerability, and safety of BIB in the treatment of obesity. METHODS: A total of 173 Saudi obese patients [mean+/-SD age 34.5 +/- 11.6 years, 58 (33.5%) were men] who underwent BIB (InaMed Corporation, California, USA) insertion were followed up clinically, biochemically, and endoscopically for 6-12 months. The mean+/-SD baseline body weight, excess weight, and body mass index (BMI) were 123.5 +/- 39.6 and 68.9 +/- 40.0 kg and 46.7 +/- 14.1 kg/m(2), respectively. Associated dietary control, exercise, and medical treatment were used in 67 (38.7%), 60 (34.7%), and 3 (1.7%), respectively. RESULTS: BIBs were safely and successfully inserted in 15.1 +/- 6.2 min, filled with 626.2 +/- 41.7 ml methylene blue solution, removed after a period of 189.7 +/- 68.3 days, within 14.1 +/- 6.3 min. BIB was not tolerated for 6 months in 33 (19.8%) patients. Body weight and BMI at 6 and 12 months postinsertion were significantly reduced to 112.5 +/- 35.7 kg and 43.1 +/- 13.1 kg/m(2), and 110.7 +/- 34.5 kg and 42.3 +/- 12.6 kg/m(2), respectively (p < 0.01 versus baseline by one-way ANOVA). Furthermore, the mean absolute weight loss and mean percentage excess weight reduction (EWR) at 6 and 12 months post-BIB insertion were 13.5 +/- 13.5 kg and 19.5 +/- 21.8, and 14 +/- 18.5 kg and 18.0 +/- 25.8, respectively. No mortality or major complications has occurred. EWR of >or=25% occurred in 24.1% and 30.1% of patients at 6 and 12 months postinsertion, respectively. CONCLUSION: BIB is a safe, simple, and potentially efficient procedure that is well-tolerated by the majority of patients.

Sustained virologic response to peginterferon alpha-2a and ribavirin in 335 patients with chronic hepatitis C: a tertiary care center experience.

BACKGROUND/AIM: This retrospective study assessed the efficacy, safety, and the predictors of sustained viral response (SVR) to a 48-week-course of peginterferon alpha-2a (Pegasys) and ribavirin combination therapy in 335 consecutive Saudi patients with chronic hepatitis C virus (HCV) infection. MATERIALS AND METHODS: Clinical, biochemical, and virological parameters were collected at time 0 (pretreatment) and at 12, 24, 48, and 72 weeks posttreatment. The mean +/- SD age was 49.1 +/- 13.0 years; 229 (68.4%) were males, mean +/- SD body mass index was 27.8 +/- 7.4, 85 (25.4%) were diabetic, 25 (7.5%) had renal impairment, 136 (40.6%) had previously received interferon +/- ribavirin therapy, and 247 (73.7%) underwent pretreatment liver biopsy. Patients with genotypes 1, 2 or 3, 4 and mixed genotype were 60 (22.15%), 30 (11.0%), 148 (54.4%), and 34 (12.5%), respectively. RESULTS: Early viral response (>or=2-log10 HCV-RNA decline 12 weeks posttreatment) was achieved in 253 (75.3%). Patients who completed 48 weeks of treatment were 292 (87.1%); of these, 121 (75.6%) achieved ETVR, 161 (55.1%) continued to have SVR and 60 (20.5%) had a viral relapse following end-of-treatment response, that is 48.1 and 17.9% of all patients (n = 335), respectively. Nonresponders (NR) were 71 (24.3%) patients and 43 (12.8%) were unable to complete treatment (due to side effects or loss to follow up). Compared to the relapsers, patients with SVR were significantly younger (P = 0.000), nondiabetics (P = 0.015), had higher serum albumin (P = 0.007), had less pretreatment inflammatory grade (P = 0.011), infected with genotypes 2 or 3 (P = 0.014), and treatment-naïve patients (P = 0.001). However, in stepwise multivariate logistic regression analysis, only treatment naiveté and low pretreatment inflammatory score were the independent predictors of SVR (P = 0.005 and P = 0.018, respectively). CONCLUSION: Combination therapy, if tolerated and completed, is effective in treating chronic HCV patients, especially those with no previous interferon therapy and lower pretreatment inflammatory grade.